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T D Anderson

Publications and source records attributed to T D Anderson.

At least 37 records · Page 2Linked to original sources
PubMed1994

Interleukin-12: a cytokine with therapeutic potential in oncology and infectious diseases.

IL-12 is a cytokine that promotes cell-mediated immunity by promoting Th1-type cytokine responses, enhancing the lytic activity of NK/LAK cells, augmenting specific CTL responses, and inducing the production of IFN-gamma. On the other hand, IL-12 suppresses the development of Th2-type cytokine responses and humoral immunity, particularly IgGl and IgE responses. It is likely that IL-12 normally plays an important role in the host defense against intracellular microbial pathogens. In addition, the administration of rIL-12 to mice has been shown to have potent therapeutic effects in several tumour and infectious disease models. IL-12 has been shown to be more efficacious than IL-2 in several murine tumour models, and toxicology studies suggest that it may have a substantially better therapeutic index. In addition, the long serum half-life of IL-12 relative to other cytokines will allow more flexibility in dosing schedules. However, future clinical trials are required to determine whether the efficacy of IL-12 seen in these experimental models is predictive for its use as an immunomodulatory drug in humans.

Animals↗
PubMed1994

Biologic effects of recombinant human interleukin-12 in squirrel monkeys (Sciureus saimiri).

BACKGROUND: Interleukin-12 is a novel heterodimeric cytokine that stimulates the proliferation of activated T and NK cells and induces lymphokine-activated killer cell activity in vitro. To investigate the biological effects of recombinant human IL-12 (rHuIL-12) in vivo, two exploratory studies were conducted in squirrel monkeys (Sciureus saimiri), which have been shown to be pharmacologically responsive to rHuIL-12 in vitro. EXPERIMENTAL DESIGN: In the first study, 18 monkeys (3/sex/group) were given daily subcutaneous injections of 0 (vehicle control), 10, or 50 micrograms/kg/day rHuIL-12 for 14 days. In the second study, 18 monkeys were given 0, 0.1, or 1 micrograms/kg/day rHuIL-12 for 14 days The animals were monitored for clinical signs, hematology and clinical chemistry changes, and sacrificed on day 15 to evaluate gross and histopathologic changes. One monkey in the high dose group was sacrificed moribund on day 14. RESULTS: Monkeys given rHuIL-12 had dose-related hematologic changes characterized by mild to moderate anemia and leukocytosis. Serum chemistry changes included hypoproteinemia, hypoalbuminemia, hypophosphatemia, and hypocalcemia. Gross pathologic findings included generalized lymph node enlargement and splenomegaly with pulmonary edema and peritoneal effusions in two high dose monkeys. Dose-related histopathologic findings included thymic cortical atrophy, splenic lymphoid hyperplasia with histiocytic hyperplasia and extramedullary hematopoiesis of red pulp, Kupffer cell hypertrophy and hyperplasia, trilineage bone marrow hyperplasia, and reactive hyperplasia of lymph nodes. Animals in the 10 and 50 micrograms/kg/day dose groups developed high titers of anti-rHuIL-12 antibodies by day 15. CONCLUSIONS: These studies indicate that rHuIL-12 is bioactive over a wide dose range and induces prominent hyperplasia of hematopoietic and lymphohistiocytic tissues in squirrel monkeys. Moreover, positive immunomodulatory activity (enhanced lymphocyte lytic activity) was detected at a dose of rHuIL-12 that is 500-fold less than the dose causing severe toxicity.

Animals↗
PubMed1993

Species differences in nucleotide pool levels of 2',3'-dideoxycytidine: a possible explanation for species-specific toxicity.

The nucleoside analogue, 2',3'-dideoxycytidine (ddC), a potent inhibitor of human immunodeficiency virus reverse transcriptase (in its anabolized triphosphorylated form), mediates virologic and immunologic improvements in AIDS patients. Clinical studies using ddC have shown various ddC-related toxicities, the most pronounced being a dose-limiting peripheral neuropathy. The dose responsiveness and manifestation of the ddC-related neuropathy vary among species, with greatest sensitivity in human > monkey > rabbit whereas mice and rats are insensitive to ddC-related neuropathy. This study has examined nucleotide pool sizes of ddCTP and its constituents (ddC, ddCMP, ddCDP) in cultured fibroblasts (human, rabbit, mouse) and freshly isolated peripheral lymphocytes (monkey, rabbit, rat, and mouse). Cells were treated with 10 microM [3H]ddC and nucleotide pool sizes analyzed by HPLC. The formation of nucleotide pools increased during the 24-hr assay period. Fibroblast pool formation of phosphorylated metabolites was significantly greater in human > rabbit > mouse. Lymphocytes demonstrated a similar pattern with monkey > rabbit > mouse = rat. Total ddC anabolite pools were also found to be significantly smaller (p < 0.05) in rodent lymphocytes than in those of rabbit or monkey, and rodent fibroblasts were smaller than those of human or rabbit (p < 0.05). These findings indicate that nucleoside phosphorylation and intracellular levels of phosphorylated metabolites may play an important role in determining species sensitivity and manifestation of ddC-related toxicity.

Animals↗
PubMed1993

Cytokine-induced changes in the leukon.

Cytokines are regulatory peptides, produced by virtually every nucleated cell type in the body, that have pleiotropic effects on hematopoietic, lymphoid, and other cell types. Cytokines usually act locally as autocrine or paracrine cellular signals intended to maintain local homeostasis but in disease states can spill over into the circulation to initiate systemic reactions. The systemic administration of high doses of recombinant cytokines is associated with a multitude of pharmacologic and toxicologic effects, frequently involving the hemolymphopoietic system. These effects may represent direct or indirect pharmacologic or hyperpharmacologic activity or may represent toxicity. The objective of this review is to present the general types of hemolymphopoietic changes associated with cytokine administration to animals and to provide examples of cytokine-induced effects on the hemolymphopoietic system.

Animals↗
PubMed1992

Effect of chronic interleukin-2 treatment on RES phagocytic activity in the rat.

The effect of chronic interleukin-2 (IL-2) injection upon reticuloendothelial system (RES) function in the rat has been determined. Seven-day treatments with two doses of human recombinant IL-2 resulted in a dramatic reduction in the phagocytic uptake of the liver and spleen, while increasing the weight of both organs. There were dramatic histological changes in the intestine, liver and spleen as well. These results suggest that the chronic use of IL-2 can result in hepatic dysfunction, which is associated with altered RES phagocytic function.

Animals↗
PubMed1992

Hematological effects of 2',3'-dideoxycytidine in rabbits.

The antiviral nucleoside analogue 2',3'-dideoxycytidine (ddC) is a DNA chain terminator and/or inhibitor of human immunodeficiency virus (HIV) reverse transcriptase. We evaluated the effects of ddC in 36 New Zealand white rabbits. Three/sex were assigned to a control group and 5 treatment groups (10-250 mg/kg/day) for 13 or 18 weeks. Blood samples were taken 1 week prior to treatment and weekly thereafter to termination with the exception of the 2 highest dose groups, where blood sample collection was terminated at week 13. Selected hematological analytes were measured weekly with the exception of prothrombin time (PT) and activated partial thromboplastin time (APTT). PT and APTT and selected biochemical analytes were measured prior to treatment, at 7 weeks, and after 13 weeks of treatment. All rabbits were necropsied. Giemsa and hematoxylin and eosin sections were prepared from methacrylate-embedded marrow. Hematological effects included decreases in red blood cell count, hemoglobin, hematocrit, and white blood cell count and increases in mean corpuscular volume and red cell distribution width. Platelets, platelet volume, PT, APTT, and mean corpuscular hemoglobin concentration values were variable or unchanged. Effects were dose-related, most were seen at 1 week, and they persisted to term. Bone marrow histopathologic changes included megalocytosis, erythroid hypoplasia, bizarre erythroid nuclear morphology, nuclear-cytoplasmic asynchrony, and increased mitotic figures. Lymphopenia caused by ddC plateaued at 2 weeks and persisted until termination. Heteropenia (neutropenia) was sporadic. Biochemical values for serum analytes were unchanged by treatment. The principal hematological effect of ddC upon the erythron was characterized as a nonregenerative macrocytic anemia with erythroid hypoplasia and megaloblastic erythropoiesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Peripheral neuropathy induced by 2',3'-dideoxycytidine. A rabbit model of 2',3'-dideoxycytidine neurotoxicity.

The nucleoside analog 2',3'-dideoxycytidine (ddC) is a potent inhibitor of the reverse transcriptase of human immunodeficiency virus and a DNA chain terminator. In clinical trials in patients with acquired immunodeficiency syndrome, ddC treatment has been associated with a dose-limiting and dose-dependent, painful, sensorimotor peripheral neuropathy. In search of an animal model for ddC-induced neurotoxicity we studied 36 New Zealand White rabbits (3 males/3 females/group) given 0, 10, 50, 100, 150, or 250 mg/kg/day of ddC, by oral intubation, for 13 or 18 weeks. Rabbits in the 150 and 250 mg/kg/day groups were sacrificed at 13 weeks because of hematopoietic toxicity. After 16 weeks, rabbits in the 50 and 100 mg/kg/day groups showed hindlimb paresis and/or gait abnormalities. Nerve conduction velocities and amplitudes in the 100 mg/kg/day rabbits were reduced by 30 to 50%. The most prominent pathologic changes in peripheral nerve and ventral roots of ddC-treated rabbits were (a) myelin splitting and intramyelinic edema, (b) demyelination and remyelination of axons, and (c) axonal loss. Treatment-related histologic lesions were not observed in spinal cord, brain, or retina. The pathology in these ddC-treated rabbits is consistent with a peripheral myelinopathy and axonopathy. This represents the first clinical, electrophysiologic, and pathologic description of an animal model of a peripheral neuropathy induced by a nucleoside analog.

Administration, Oral↗
PubMed1992

Ultrastructure of peripheral neuropathy induced in rabbits by 2',3'-dideoxycytidine.

The nucleoside analogue, 2',3'-dideoxycytidine (ddC), an inhibitor of human immunodeficiency virus reverse transcriptase, mediates virologic and immunologic improvements in acquired immunodeficiency syndrome patients. However, in clinical studies ddC treatment is associated with a dose-limiting peripheral neuropathy. The purpose of this study was to characterize the ultrastructural features of the peripheral neuropathy induced in rabbits. Rabbits received 0, 10, 50, or 100 mg/kg/day of ddC for 18 weeks. A prominent ultrastructural change induced by ddC in sciatic nerve and ventral root was separation of myelin lamellae at the intraperiod line and vacuolation and fragmentation of myelin sheaths. Many demyelinated and remyelinated axons were observed. Although pathologic alterations in Schwann cells were evident by the presence of lipid droplets and myelin figures, their formation was not considered a primary event. Axons containing abnormal cytoplasmic components were occasionally observed. Other changes included redundance of Schwann cell basal lamina and the presence of lipid droplets and/or myelin figures within endoneurial fibroblasts and macrophages. The results of this study indicate that ddC induces a myelinopathy in rabbits characterized by myelin splitting and intramyelinic edema and an axonopathy that may be secondary to the myelin changes.

Animals↗
PubMed1991

Differential release of active proteinase inhibitors by two rat mammary adenocarcinoma variants possessing different metastatic potentials.

The ability of tumor cells to express elevated levels of proteinases capable of degrading tissue matrix and basement membrane components in vitro has been correlated to their invasive and metastatic potential. Many in vitro invasion assays have been performed either in the presence of serum or with tumor cells that had been previously grown in serum. Since serum contains large amounts of active proteinase inhibitors, their presence could complicate interpretations. We have, therefore, attempted to measure the amounts of serine proteinase inhibitors released into culture medium by two rat mammary adenocarcinoma metastatic variants selected in vitro for serum-independent growth and differing in their in vivo metastatic behavior. Concentrated spent media (CSM) derived from cultures of poorly metastatic MTLn2(T42D) and highly metastatic MTLn3(T17D) tumor cells, grown in the presence and absence of fetal bovine serum (FBS) for 20-24 h, were compared for the presence of serine proteinase inhibitors capable of inactivating alpha-chymotrypsin. Our results show that when MTLn2(T42D) and MTLn3(T17D) tumor cells were exposed to FBS, the CSM of MTLn2(T42D) exhibited nearly 5-fold greater amounts of active proteinase inhibitors than that of MTLn3(T17D). The amount of proteinase inhibitory activity detected in the CSM of tumor cells not exposed to FBS was not eliminated but declined by 82% and 37% for MTLn2(T42D) and MTLn3(T17D), respectively. Analysis for enzyme-inhibitor (E-I) complex formation by nonreducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by autoradiography confirmed the kinetic results and revealed that the major inhibitor present in CSM/FBS of both variants forms a heat- and sodium dodecyl sulfate-stable E-I complex with an apparent molecular weight of approximately 79,000, identical to that formed when FBS or purified alpha 1-proteinase inhibitor is incubated with [alpha-125I]chymotrypsin. E-I complexes with apparent molecular weights of 44,000 and 50,000 were formed from CSM/bovine serum albumin of MTLn3(T17D) and MTLn2(T42D), respectively, that were not detected when [alpha-125I]chymotrypsin was incubated with bovine serum albumin. We infer from these observations that, in culture, poorly metastatic MTLn2(T42D) tumor cells, as compared to their highly metastatic MTLn3(T17D) counterparts, exhibit an increased capacity to retain and subsequently release significantly greater amounts of serum-derived active proteinase inhibitors. Moreover, the detection of proteinase activity by kinetic analysis and E-I complexes by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography in CSM prepared from cultures not exposed to FBS indicates that both variants have the capacity to produce their own inhibitors.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗
PubMed1991

Comparison between effects of interleukin-1 alpha administration and sublethal endotoxemia in primates.

Interleukin (IL)-1 is an early mediator of host response to inflammation, although its contribution to individual components of the acute phase reaction is still unclear. To evaluate how the hemodynamic, metabolic, and hormonal responses to sublethal endotoxemia compare with IL-1 administration, baboons received intravenously either lipopolysaccharide (LPS) or 0.1, 10, or 100 micrograms/kg IL-1 alpha. LPS induced an early tachycardia and a fall in mean arterial pressure, as well as lacticacidemia and hypoaminoacidemia. Similar hemodynamic and metabolic changes were seen with 10 or 100 micrograms/kg of IL-1 alpha. An increase in adrenocorticotropic hormone and fall in serum iron were induced by IL-1 alpha but not by LPS. Plasma tumor necrosis factor-alpha (TNF-alpha) was not measurable after IL-1 alpha administration, whereas LPS induced a monophasic TNF-alpha response. IL-6 levels were significantly greater after LPS than IL-1 alpha administration. Histopathological lesions, similar in LPS- and 100 micrograms/kg IL-1 alpha-treated groups, were present only in the adrenal cortex. We conclude that many, but not all, of the effects of sublethal endotoxemia can be replicated by IL-1 alpha administration, and these responses are dose dependent.

Amino Acids↗
PubMed1990

Peroxidase-antiperoxidase and immunogold labeling of Salmonella typhimurium and Salmonella choleraesuis var kunzendorf in tissues of experimentally infected swine.

Peroxidase-antiperoxidase immunoenzymatic labeling and immunogold labeling techniques were evaluated for microscopic detection and location of Salmonella organisms in tissues of experimentally infected swine. Salmonella typhimurium and Salmonella choleraesuis var kunzendorf were labeled specifically by the peroxidase-antiperoxidase technique in paraffin-embedded tissues of infected swine for conventional light microscopy and by postembedding immunogold labeling on ultrathin sections for electron microscopy. Salmonella typhimurium had a low tendency to invade the enteric mucosa and did not reveal any predilection for a specific intestinal location. Salmonella choleraesuis var kunzendorf, however, was located preferentially in colon and on the luminal surface of ileal M cells of Peyer patches and had a tendency to invade the enteric mucosa there.

Animals↗
PubMed1989

Regulation of hemopoiesis in myelosuppressed mice by human recombinant IL-1 alpha.

Human rIL-1 alpha was shown to be a potent stimulus of granulopoiesis in mice that have been myelosuppressed with cyclophosphamide. Stimulation of granulopoiesis was demonstrated in IL-1-treated mice by an accelerated recovery of granulocyte-macrophage colony-forming cells, bone marrow and splenic granulocytic hyperplasia, and a profound granulocytosis. Granulopoiesis was stimulated by IL-1 in a dose-dependent manner at doses ranging from 0.5 to 50 micrograms/kg. Maximal increases in granulocytes were observed after 4 days of IL-1 treatment. Mice treated with IL-1 also exhibited increased splenic megakaryopoiesis with a resultant increase in the number of peripheral blood platelets. In contrast to these positive effects on hemopoiesis, bone marrow, but not splenic, erythropoiesis was depressed in IL-1-treated mice. IL-1 effects were observed in mice treated with a wide dose range (50 to 300 mg/kg) of cyclophosphamide, with optimal effects occurring at a dose of 200 mg/kg. The doses of IL-1 leading to enhanced granulopoiesis caused only minor and transient changes in selected clinical chemistry parameters and caused no toxicities that were evident by histologic examination of tissues. The stimulation of granulopoiesis in the absence of overt toxicity suggests that IL-1 may be useful clinically to enhance the recovery of granulocytes in myelosuppressed patients.

Animals↗
PubMed1989

The therapeutic activity in cancer of IL-2 in combination with other cytokines.

Animal studies have been carried out to assess the antitumour efficacy of recombinant interleukin-2 (rIL-2) in combination with other cytokines. In several murine tumour models, rIL-2 in combination with recombinant alpha interferon (rIFN-alpha) elicits a potent antitumour response which is often greater than that which can be reached with the individual agents at non-toxic doses. By contrast, recombinant gamma interferon (rIFN-gamma) usually fails to potentiate the antitumour response to rIL-2. Recombinant alpha tumour necrosis factor (rTNF) can synergize with rIL-2 in some circumstances, but, as with the rIL-2/rIFN-alpha combination, the correct regimen is critical for generating a potent response without overt toxicity. Although appropriate cytokine combinations can lead to markedly enhanced tumour infiltration by lymphocytes, it is not clear that only a single type of lymphocyte is invariably involved in the antitumour response or, for that matter, the toxic side effects; nor has the mechanism of action of any of the cytokines in the therapeutic action been unequivocally elucidated. Finally, results of early clinical studies appear to be consistent with results in preclinical models: promising clinical responses to the combination of rIL-2 and rIFN-alpha have already been observed and further study is merited.

Animals↗
PubMed1989

Toxicity of human recombinant interleukin-2 in rats. Pathologic changes are characterized by marked lymphocytic and eosinophilic proliferation and multisystem involvement.

To characterize the subacute toxicologic and pathologic effects of human recombinant interleukin-2 (rIL-2) in rats, rIL-2 was administered to rats at doses ranging from 3.0 to 150 X 10(6) units/kg/day for 14 to 16 days, in once or twice daily dosing regimens by intravenous or intraperitoneal dosing routes. The hematologic, clinical chemical, gross pathologic and histopathologic findings were determined. Rats given rIL-2 had dose- and regimen-related incidences of hemolytic anemia, lymphocytosis, neutrophilia, eosinophilia, thrombocytopenia, increased hepatic transaminases, hyperbilirubinemia, hypoalbuminemia, ascites and pleural effusions, and prerenal azotemia. Marked lymphoid infiltration of the liver and eye were associated with hepatocyte necrosis and retinal damage. Eosinophilic infiltration of the adrenal medulla was associated with medullary cell necrosis. Other histopathologic changes included infiltration of multiple tissues by eosinophils and/or lymphocytes, lymphoid hyperplasia and splenic extramedullary erythropoiesis and eosinopoiesis. Hematologic, clinical chemistry, and histopathologic changes were of markedly greater severity in rats receiving rIL-2 twice daily as compared with those receiving the same total dose of rIL-2 once daily. Mortality in severely affected rats was secondary to severe anemia and/or hepatic damage. The results of these studies demonstrate that the major pathologic changes associated with rIL-2 administration in rats are characterized by marked tissue infiltration with lymphocytes and eosinophils. Many of the adverse effects of rIL-2 administration to rats are similar to those reported in humans receiving rIL-2 immunotherapy and the results confirm that the rat is an appropriate species in which to study selected aspects of rIL-2 toxicity.

Adrenal Medulla↗
PubMed1988

Role of asialo-GM1-positive lymphoid cells in mediating the toxic effects of recombinant IL-2 in mice.

Studies were performed to characterize the toxic effects of human rIL-2 in mice and to examine the mechanism of toxicity. Intraperitoneal administration of rIL-2 at doses greater than or equal to 2 X 10(6) U/kg twice each day for greater than or equal to 4 days led to toxicity in several strains of mice. The toxic effects of rIL-2 included the vascular leak syndrome (manifested by pulmonary edema, pleural effusions, and ascites), elevated hepatic transaminases, hyperbilirubinemia, hypoalbuminemia, pre-renal azotemia, anemia, thrombocytopenia, mild eosinophilia, and death. Marked lymphoid cell infiltration of pulmonary and hepatic vasculature was present in mice suffering from rIL-2 toxicity, and the pleural and ascitic fluids also contained high numbers of mononuclear cells. Mononuclear cells isolated from the pleural fluids and livers of these mice were 74 to 98% Thy-1+, 55 to 83% asialo-GM1+, 29 to 45% Lyt-2+, and less than 10% L3T4+. These cells possessed potent lymphokine-activated killer (LAK)-like activity in that their ability to lyse cells of the NK-resistant P815 mastocytoma line was 10- to 100-fold higher on a per cell basis than splenocytes from the same animals. A correlation was found between the dose level, duration, and frequency of dosing with rIL-2 required to induce pleural effusions and hepatotoxicity and the dosage regimens required to produce the LAK-like cells in the pleural cavities and livers, respectively, of rIL-2-treated mice. Moreover, treatment of mice with anti-asialo-GM1 (anti-ASGM-1) antiserum in vivo at the same time they were receiving toxic doses of rIL-2 abolished or greatly reduced the severity of the vascular leak syndrome and hepatotoxicity and significantly prolonged the survival of the mice. Administration of anti-ASGM-1 to mice receiving toxic doses of rIL-2 resulted in a marked reduction in the LAK-like cytolytic activity of their pleural and liver lymphoid cells and a corresponding reduction in the percentage of ASGM-1+ cells in pulmonary and hepatic lymphoid infiltrates. Nevertheless, the overall extent of pulmonary and hepatic lymphoid infiltration, as well as other consequences of rIL-2 administration, including splenomegaly, hypoalbuminemia, eosinophilia, and thrombocytopenia, were not diminished as a result of anti-ASGM-1 treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗